Introduction

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory sinonasal disease that is estimated to affect between 0.5 and 4.5% of the general population, with a proven significant impact on patient’s quality of life (QoL) and a high economic cost to healthcare systems [1]. Initial treatment involves nasal rinses and intranasal steroids, leaving systemic corticosteroids for the exacerbations, constituting the so-called appropriate medical treatment (AMT) [2,3,4]. In patients whose AMT is insufficient to achieve symptom control, endoscopic sinus surgery (ESS) has been proposed as a suitable alternative [5]. However, there is no consensus on the optimal surgical strategy in CRSwNP, and polyp recurrences remain a significant limitation of this therapeutic approach [6]. Moreover, since the guideline’s recommendations on the management of CRSwNP are constantly changing, surgery has become a fundamental criterion for indicating the recent treatment option with biological therapies [7].

Comorbidities, such as late-onset asthma and nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD), or a history of re-interventions, are associated with poorer disease control and often account for the failure of the medical and surgical treatments [8]. Furthermore, the increasing knowledge of the underlying mechanisms that produce mucosal inflammation in CRSwNP (the mucosal concept) [9•] and the description of several biomarkers, such as immunoglobulin E (IgE), eosinophilic cationic protein (ECP), or interleukins (IL) 4, 5, and 13, have led the description of subjacent inflammatory endotypes and consequent phenotypes and allow the application of the precision medicine paradigm in the management of CRSwNP patients [10, 11]. In this sense, the advances in the knowledge of the type 2 endotype have allowed the development of new and more extended surgical approaches to manage these disease’s severe and recalcitrant phenotypes [12, 13]. This change in the CRSwNP paradigm has meant that techniques such as full-house or reboot surgery, based on wide resection of bony sinus structures and the treatment of mucosa lining the sinonasal cavity, have been analyzed and compared with other techniques to assess if they are associated with more favorable surgical outcomes and improved QoL, in addition to lower relapse rates [14, 15••].

Our group home-grown classification of the different techniques of ESS published to date, including a thorough description of their characteristics attending to the surgical modification performed on the anatomic structures of the sinonasal cavity, is shown in supplementary files (Table S1).

We have also shown that an extended autologous mucosal graft from the nasal floor positioned in the ethmoidal roof (mucoplasty) associated with reboot surgery may provide an added benefit to endoscopic and QoL outcomes in CRSwNP patients with type 2 phenotype by improving not only the healing but also the post-surgical inflammatory pattern with a regenerative role [16••].

The objective of our study is to systematically review the expected benefit of extended endoscopic sinus surgery (EESS) versus other approaches and the role of mucoplasty as a conceptually regenerative option in the surgical management of severe CRSwNP patients.

Material and Methods

This systematic review has been reported following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [17] (supplementary files—Table S2 contains the PRISMA checklist fulfilled). No review protocol was registered for this study.

Research Question

We aimed to answer the following research question: What are the advantages of adding mucoplasty to reboot surgery in treating severe chronic rhinosinusitis with nasal polyp patients versus the medical or surgical standard of care?

Search Strategy

The search strategy was designed using the PICOTs framework:

  • Participants: Severe CRSwNP patients older than 18, non–responders to adequate medical treatment who undergo ESS.

  • Intervention: Eligible interventions included extended ESS (e.g., nasalization, complete, radical, full-house, reboot, reboot) with or without mucoplasty.

  • Comparators: Standard of care of medical or surgical treatment, following international guidelines [2, 3].

  • Outcomes: Quality of life (QoL) and/or symptom scale improvement, changes in nasal endoscopy scores and/or computed tomography (CT) scan scores.

  • Timing and Setting: With no limitations.

According to PRISMA statement recommendations, we searched in the following databases: PubMed, The Cochrane Library for Cochrane Reviews, Embase via Elsevier, Web of Science, and Scopus from inception until May 2023. The search strategy is described in supplementary files (Table S3). To supplement the database search, we manually checked the reference lists of the included studies, performed a backward citation analysis, and completed a forward citation analysis.

Eligibility Criteria

Inclusion criteria for studies to select were articles written in English, which type of design has been clinical trials, cohort studies, case–control studies, cross-sectional studies, or case-series studies published in peer-reviewed journals.

Exclusion criteria were studies dealing with localized and/or systemic CRSwNP, bilateral inflammatory disease but without nasal polyps, unilateral surgical approaches, or CRSwNP in treatment with monoclonal antibodies during the study period.

Study Extraction, Categorization, and Analysis

Screening by title and abstract was conducted by three authors (DMJ, RML, JMS) independently. After title and abstract screening and discard, full texts were retrieved for the remaining articles. Two authors (DMJ, RML) reviewed the full texts against the inclusion criteria. Discrepancies were resolved by consensus.

A standardized form (initially piloted on six included studies) was used for data extraction of characteristics of studies, outcomes, and risk of bias. Data extraction was conducted by two authors (DMJ, RML). Extracted variables encompassed: sample size, age, gender, comorbidities such as asthma, NSAID-exacerbated respiratory disease, or proven allergic sensitization, type of surgery, and the primary outcomes in terms of QoL (Sinonasal Outcomes Test–22), symptom severity (visual analogue scale (VAS), total nasal symptom score (TSS)), nasal endoscopy scores (nasal polyp score (NPS), Meltzer scale, total polyp score (TPS), modified Lund-Kennedy (MLK) scale), or sinus CT scan (Lund Mackay (LM) scale).

Assessment of Study Quality and Risk of Bias

Studies selected for the systematic review were assessed about quality using the Oxford Centre for Evidence-Based Medicine Levels of Evidence [18]. The risk of bias was assessed using the Quality Assessment of case series studies checklist from the National Institute for Health and Clinical Excellence (Fig. 2 and Supplementary Table S4) [19]. Three authors (DMJ, RML, JMS) independently performed the evaluation, and consensus solved discrepancies.

Statistical Analysis

Meta-analyses were not possible due to the outcomes’ high heterogeneity between studies, so only qualitative analysis was performed. Three authors (DMJ, RML, JMS) discussed the magnitude and relevance of the effects assessed for the qualitative analysis. Discrepancies were solved by consensus, and these discussions were reflected in the discussion section.

Superior postoperative outcomes for severe CRSwNP patients were considered when a more considerable improvement in the QoL or symptoms scales was shown (SNOT-22, VAS, or other analyzed scales), as well as when decreases in the values of endoscopic and radiological scales were observed after surgery (NPS, Meltzer scale, TPS, MLK scale, and LM score). Other features of interest in the qualitative evaluation of the studies were tissue and peripheral blood cell counts, measurements of tissue biomarkers, the control of lower airways comorbidities (asthma or N-ERD), the rates of polypoid recurrences, the need for revision surgery, and changes in the assessment of smell.

Results

The bibliographic search for the systematic review was performed on May 23, 2023, and identified 1067 potentially relevant studies. After removing duplicates and applying the inclusion and exclusion criteria, 13 articles and a study yet to be published from our group were included in qualitative synthesis for the data extraction. The selection process was recorded in sufficient detail to complete a PRISMA flow diagram (see Fig. 1).

Fig. 1
figure 1

PRISMA flow diagram. Abbreviations: CRS, chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyps; QoL, quality of life

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All included articles had relevance to the subject of this review. Two were non-randomized controlled clinical trials, one a prospective case–control study, four retrospective case–control, three prospective case series, and the remaining four papers were retrospective case series.

Table 1 describes the included studies’ quality characteristics and features in terms of follow-up period, sample size, age of the sample, sex, asthma and N-ERD prevalence, proven allergic sensitization, and history of previous ESS. Figure 2 summarizes the assessment risk of bias using the Quality Assessment of case series studies checklist from the National Institute for Health and Clinical Excellence (published as Appendix F).

Table 1 Summary table of demographics characteristics and biomarkers distribution of the articles included in this review
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Fig. 2
figure 2

Quality Assessment of case series studies checklist from the National Institute for Health and Clinical Excellence (Appendix F) applied to this systematic review. The color graphic represents the answer to each checklist question from 1.1 to 5.2 (27 questions); the specific answers are shown in Supplementary Table S4

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Table 2 summarizes the main findings of the qualitative analysis of included articles in this systematic review, including the outcomes reported per article. EESS reflected better results in the QoL questionnaires, polypoid growth scales, and better radiological imaging measures than functional surgeries. Recurrence rates, disease-free time, control of comorbidities, and olfaction study outcomes were also higher associated with more extended approaches. Disparate results were found in the analysis of molecular biomarkers, cell counts, and endoscopic findings of edema and nasal discharge.

Table 2 Summary table of the main characteristics and results of the articles included in this review
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Discussion

This systematic review of studies investigating the role of EESS and mucoplasty added to reboot surgery has retrieved 14 studies, all with promising results for extended ESS for the treatment of severe CRSwNP patients, but also concluding that more high-quality surgical studies are needed to accurately define these results and the benefit of adding mucoplasty. Despite this, incorporating mucoplasty as a regenerative approach may be associated with better outcomes than other EESS in managing severe CRSwNP patients by improving healing and post-surgical quality of life versus reboot surgery alone.

Selecting suitable surgical treatment for severe CRSwNP remains controversial in patients who do not achieve disease control with appropriate medical treatment. A wide range of ESS techniques, functional/targeted [26, 29] or extended surgeries [15••, 24, 27], with different extensions and nuances, has redefined their selves focused on advances in the pathophysiological understanding of this disease (Table S1 supplementary files). Recent studies assessing extended approaches, such as reboot surgery [15••], regenerative surgery (reboot surgery plus mucoplasty) [16••, 30], or extended full-house surgery [14], show that these approaches are likely to yield improved clinical and QoL outcomes compared to functional approaches in the more severe patients. However, these studies are qualified as having low levels of evidence due to the risk of bias related to the absence of placebo, non-randomization, and/or the high heterogeneity in their design [31].

The current different surgical techniques proposed thus far do not yet allow optimal disease management, submitting high polypoid recurrences [8, 32]. Even so, EESS has been proposed as a more effective approach to achieving lower revision rates [6, 13, 33]. The anatomical landmarks for more extended resections have already been emphasized [14, 24]. These approaches involve removing all nasal polyps and septa of the nasal and paranasal sinuses to achieve broad exposure while preserving the macroscopically healthy mucosa as a substrate for local healing. In contrast, newer approaches, such as reboot surgery [15••], focus on the newly argued hypothesis of the mucosal concept [9•], and propose resecting both the pathological and the surrounding healthy mucosa. This hypothesis assigns a transcendental role to the mucosal barrier in the inflammatory burden of CRSwNP pathophysiology, in which biomarkers contributing to polypoid recurrence have been identified [13, 34]. Mucoplasty as a regenerative surgery seeks to improve local control of the inflammatory burden after completely resecting the mucosa (reboot surgery) and by positioning a free mucosal graft from the floor of the nostril, which has different molecular and cellular features, with a lower tendency to polyp growth, adding these so-called regenerative properties [16••, 35]. Our group has conducted a new line of investigation to support the hypothesis of mucoplasty as a regenerative approach. The role of fibroblasts in the pathogenesis of CRSwNP, especially in the remodeling of the mucosa, is the basis for this hypothesis. In a recently published study, our group has shown that nasal polyp fibroblasts are a source of pro-inflammatory signaling that reinforce type 2 inflammation in CRSwNP [35].

Consequently, it could be targeted for therapeutic purposes as a potential novel source of inflammatory signaling [36]. Our experiments have also shown that the distribution of inflammatory cells differs in different locations of the nasal cavity, as well as in the polypoid mucosa and healthy mucosa [34]. This observed disparity may further strengthen the rationale for considering the nasal cavity floor mucosa as a suitable candidate for mucosal transplantation added to reboot surgery, arguing a better graft’s inflammatory and healing properties and supporting the concept of regenerative surgery. Additional tissue and molecular analyses of the inflammatory changes experienced by the mucosal graft after its placement in the ethmoidal roof are required to evaluate the functionality of these new findings and to strengthen the role of mucoplasty in sinonasal mucosal healing and healthy regeneration. More studies are needed to demonstrate the results of bilateral mucoplasty associated with reboot surgery in clinical practice, which will highlight this technique’s choice in managing severe CRSwNP and its recurrences.

The advances in the knowledge of the molecular basis of CRSwNP inflammation and the different related phenotypes have led to a precision medicine approach for diagnosing and managing CRSwNP patients [4, 11, 12]. There have been shown that patients who require revision surgeries present worse values for tissue, nasal secretion, and peripheral blood T2 phenotype biomarkers such as IL-5, IL-5 receptor alpha, and ECP [22]. Something similar was concluded concerning higher eosinophil counts in tissue and peripheral blood in patients with a tendency to polypoid recurrence [6, 37]. However, these findings seem controversial as they disappear in the long-term follow-up [21]. Studies assessing the efficacy of surgery in CRSwNP have underscored the need for biomarkers that define severe, uncontrolled, and recurrent disease to select the adequate surgical technique for each phenotype [12, 13, 38]. This enables the proposal for various extended approaches and complementary surgical procedures for patients exhibiting the more severe type 2 inflammatory endotype, such as reboot surgery adding mucoplasty, to improve their clinical outcomes and strengthen the paradigm of precision surgery [15••, 16••].

Results in our systematic review show that some extended approaches targeting the different lamellas and mucosa reach superior results in increasing QoL scores and symptom control in severe CRSwNP (Table 2). Our group has also shown that endonasal mucoplasty, complementary to reboot surgery, improves short- and medium-term outcomes versus isolated extended techniques (i.e., reboot surgery) [16••, 39]. First reports show that these mucosal grafts were used unilaterally with better local healing than the contralateral nostril in the short term [30, 39]. Subsequently, a prospective cohort study with bilateral mucoplasty showed hopeful outcomes in 54 patients with a type 2 inflammatory phenotype. An increase of up to 22.6 ± 6.3 units in the SNOT-22 QoL questionnaire was observed when using mucoplasty compared to patients who underwent only reboot surgery [16••]. These outcomes may be attributed to the early and sustained healing, facilitated by a regenerative process initiated by the mucosal autograft placed in the ethmoidal roof, with distinct cellular, molecular, and reparative features [35].

On the other hand, a significant decrease in polyp size was observed in all studies included in our systematic review, with a higher improvement in patients undergoing extended approaches, being consistent among published articles, with better average NPS values in medium- and long-term follow-up after EESS [16••, 20, 21], compared to worse results after functional surgeries [6, 26]. Recovery in polypoid size, edema, and nasal discharge have also been found by other authors with different extended approaches, such as complete [24] or full-house surgery [23], but not being significantly superior in extended versus functional ESS when analyzing endoscopic modified Lund Kennedy scale scores at short- or medium-term follow-up. Although significant enhancements in endoscopic scores were observed in EESS, no significant differences have been found among different types of surgeries in the long-term scores [6, Martin-Jimenez et al. - data not published]. The heterogeneity in study samples and the inaccurate surgical technique description may justify this variability. Moreover, post-surgical polypoid recurrences of over 40% have been reported, compared to 80–85% for edema at medium and long term [6, 23, 24, 32].

There has been shown that CRSwNP frequently appears alongside other respiratory inflammatory diseases such as asthma or N-ERD with a common underlying pathophysiology [40, 41]. The coincidence of bronchial and sinonasal type 2 inflammatory disease phenotype is a marker of poor control and higher severity for both diseases [11, 12]. Our group has recently reviewed a retrospective cohort of 274 patients with severe CRSwNP treated surgically with extended or functional ESS. We found an OR of 6.49 (95% CI 1.70, 24.84) for achieving an increase of at least 12 points in SNOT-22 scores comparing EESS vs FESS, and this improvement was independent of the asthmatic status of patients [Martin-Jimenez et al. - data not published]. DeConde et al. have already published a series of patients who underwent functional or extended ESS, finding no differences in surgical outcomes for CRSwNP in asthmatic vs no asthmatic patients [24]. This has also been shown in studies with longer-term follow-ups of CRSwNP patients treated surgically in which authors did not find differences in QoL outcomes in the subgroup of asthmatic patients compared to no asthmatic group [21]. These findings highlight the role of different types of surgery, indicating that surgical extension may lead to a significant role in achieving improved clinical and QoL outcomes, irrespective of comorbidities [6, 16••, 42].

New biologic drugs recently assessed for treating severe type 2 CRSwNP patients who do not achieve control even after surgery have been shown to address results in a way previously unattainable by medical and surgical therapy [43]. However, its cost-effectiveness still needs to be improved [44, 45]. A better efficiency related to ESS against biological drugs has been shown for achieving symptom control and improving QoL in the short- and medium-term [46,47,48]. In addition, experts groups, International Consensus, and Clinical Guidelines continue to advocate surgery before the use of these biological drugs [2,3,4, 7] and published results from clinical trials and real-life studies continue to demonstrate better outcomes in patients undergoing biological drugs after ESS versus those obtained by the treatments in isolation [49, 50]. However, surgical timing remains an ongoing topic of discussion.

Limitations

The main limitation of our review is the impossibility of performing a meta-analysis of data, carrying out only a qualitative analysis, due to the high heterogeneity and low quality of the studies included. Our results are also limited by the need for a more scientific quality of the studies involving surgical procedures due to the nuances of each technique from an anatomical point of view, describing different extensions in the resection of the lamellae and the differences in the treatment of the nasal mucosa. This issue highlights the need for a consensual classification that allows us to accurately describe the action on the lamellae, the ostium, the extension in the resection of the septa, and the mucosa treatment.

Furthermore, the absence of randomized placebo-controlled studies, subject to the difficulties of using a placebo, and the ethical limitation of the indication of different techniques in patients with similar baseline characteristics inherent to surgery studies, implies that our results lack sufficient scientific evidence to be able to draw conclusions and draw up clinical guidelines.

Finally, the clinical outcomes associated with the use of mucoplasty in an environment where new advances in the cellular and molecular understanding of the inflammatory response in CRSwNP patients are modulating targeted therapies compel the development of a deeper line of investigation of the markers that define the peculiarities in the behavior of the nasal mucosa, thorough the different locations within the nasal fossa and paranasal sinuses. The new results associated with the study of fibroblasts and the other markers that modulate the inflammatory response may be the key to understanding the advantages of bilateral mucoplasty in treating severe CRSwNP.

Conclusions

Our systematic review shows promising results for extended endoscopic sinus surgery with added mucoplasty in managing severe chronic rhinosinusitis with nasal polyp patients. The low quality of the current evidence found in this review does not allow to set robust recommendations about the most appropriate option for surgical treatment. There is a need for high-quality studies on phenotyping these patients to select those who will benefit more from each medical and surgical management option, including the combination of both, from a precision medicine point of view, including long-term efficiency as an essential outcome.